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J. Biol. Chem., Vol. 283, Issue 38, 25786-25793, September 19, 2008

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Exendin-(9–39) Corrects Fasting Hypoglycemia in SUR-1^–/– Mice by Lowering cAMP in Pancreatic β-Cells and Inhibiting Insulin Secretion^*

Diva D. De León¹, Changhong Li, Madeleine I. Delson, Franz M. Matschinsky, Charles A. Stanley, and Doris A. Stoffers^¶2

From the Division of Endocrinology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, the Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and the ^¶Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Congenital hyperinsulinism is a disorder of pancreatic β-cell function characterized by failure to suppress insulin secretion in the setting of hypoglycemia, resulting in brain damage or death if untreated. Loss-of-function mutations in the K_ATP channel (composed of two subunits: Kir6.2 and SUR-1) are responsible for the most common and severe form of congenital hyperinsulinism. Most patients are unresponsive to available medical therapy and require palliative pancreatectomy. Similar to the human condition, the SUR-1^–/– mouse is hypoglycemic when fasted and hyperglycemic when glucose-loaded. We have previously reported that the glucagon-like peptide-1 receptor antagonist exendin-(9–39) raises fasting blood glucose in normal mice. Here we examine the effect of exendin-(9–39) on fasting blood glucose in SUR-1^–/– mice. Mice were randomized to receive exendin-(9–39) or vehicle. Fasting blood glucose levels in SUR-1^–/– mice treated with exendin-(9–39) were significantly higher than in vehicle-treated mice and not different from wild-type littermates. Exendin-(9–39) did not further worsen glucose tolerance and had no effect on body weight and insulin sensitivity. Isolated islet perifusion studies demonstrated that exendin-(9–39) blocked amino acid-stimulated insulin secretion, which is abnormally increased in SUR-1^–/– islets. Furthermore, cAMP content in SUR-1^–/– islets was reduced by exendin-(9–39) both basally and when stimulated by amino acids, whereas cytosolic calcium levels were not affected. These findings suggest that cAMP plays a key role in K_ATP-independent insulin secretion and that the GLP-1 receptor is constitutively active in SUR-1^–/– β-cells. Our findings indicate that exendin-(9–39) normalizes fasting hypoglycemia in SUR-1^–/– mice via a direct effect on insulin secretion, thereby raising exendin-(9–39) as a potential therapeutic agent for K_ATP hyperinsulinism.

Received for publication, June 6, 2008 , and in revised form, July 15, 2008.

^* These studies were supported by an American Diabetes Association Career Development Award (to D. A. S.), Pediatric Endocrine Career Development award in Diabetes Research K12 DK063682, Career Development Award K23-DK073663, and a Pilot and Feasibility grant from the Penn Diabetes Center P30 DK 019525 (to D. D. L.) and R01DK53012 (to C. A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Division of Endocrinology/Diabetes, Dept. of Pediatrics, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104. Tel.: 215-590-3420; Fax: 215-590-1605; E-mail: deleon{at}email.chop.edu. ²To whom correspondence may be addressed: Division of Endocrinology, Diabetes and Metabolism, Dept. of Medicine, University of Pennsylvania School of Medicine, Clinical Research Bldg. 611 B, 415 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-573-5413; Fax: 215-898-5408; E-mail: stoffers{at}mail.med.upenn.edu.

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